Disordered Differentiation of Tubal Epithelia: Setting the Stage for Neoplastic Transformation
Abstract
Epithelial ovarian cancer is the most lethal gynecologic malignancy, responsible for an estimated 14,000 deaths per year in the U.S. Most patients initially respond well to chemotherapy, but even with the advent of PARP inhibitor therapies, relapse is common and there are few therapeutic options that provide a long-term sustained response for recurrent disease. Methods to prevent ovarian cancer from occurring undoubtedly offer the most efficient route to reducing deaths from ovarian cancer, while also enabling patients to avoid the grueling burden of surgery and chemotherapy needed to treat ovarian cancer. Oral contraceptive pills are currently the only known drug that can prevent ovarian cancer. Oral contraceptives are very effective at preventing ovarian cancer later in life, reducing a woman’s risk of developing ovarian cancer by around 50 percent. However, oral contraceptives are not well tolerated by all women and are not compatible with childbearing. Additional options for chemoprevention are needed, particularly treatments that can be effective after menopause, in contrast to oral contraceptives that only offer protection against ovarian cancer if taken before the menopause. It is now widely understood that the majority of high-grade serous ovarian cancers derive from cells lining the fallopian tube. Research by our laboratories and others has shown that, in women with inherited mutations in genes such as BRCA1 that confer a high risk of ovarian cancer, fallopian tube cells fail to fulfill the normal cellular life cycle and become stuck in a state that is more prone to carcinogenesis. We believe that this failure of fallopian tube cells to properly differentiate explains, at least in part, why these women are more at risk of ovarian cancer. Similar changes also occur in post-menopausal women, albeit to a lesser extent. The overarching idea underlying this project is that, if we can force these cancer-prone cells to complete the normal differentiation process that brings them into a less cancer prone state, we could then effectively eliminate a woman’s risk of ovarian cancer. Our long-term goal is to develop an oral drug that could be taken around the time of menopause to force the normal differentiation process to occur and prevent ovarian cancer from occurring. This represents an entirely new paradigm for ovarian cancer prevention and is conceptually linked to the highly effective differentiation therapy for acute promyelocytic leukemia, which induces a complete remission in most patients due to forced differentiation of leukemic cells. The likelihood of success of this pilot project is high, as it is based on strong preliminary data and all of the new and innovative technological approaches we propose to use are already optimized in our laboratory. We are leaders in the field of single-cell genomic analysis of human fallopian tubes and have developed a creative new protocol to apply the same technology to tissues removed from carriers of high-risk mutations, while not affecting the standard-of-care pathologic examination that usually prevents the application of such genomic technologies to these tissues. In addition, we have created three-dimensional culture models of fallopian tubes that closely mimic the architecture of human tissues in the body and mean that the results of these assays are more likely to successfully translate into the clinic. Furthermore, collaborations are in place with drug development experts and clinical trialists to expedite clinical translation of the findings of this project. Relevance: This research is closely aligned to one of the three ongoing goals of the Ovarian Cancer Research Program, which is to promote research that focuses on cancer risk and primary prevention. This initial project focuses on BRCA1 germline mutation carriers, as these individuals have the greatest risk of developing ovarian cancer; therefore, we can more efficiently identify
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210143
Entities
People
- Kate Lawrenson
Organizations
- Cedars-Sinai Medical Center
- United States Army